Project Summary/Abstract Pneumococcal conjugate vaccines (PCVs) administered to children have nearly eliminated both pneumococcal disease (e.g. pneumonia, septicemia) and colonization caused by serotypes in the vaccines. The vaccine has reduced disease rates not only in vaccinated children but also in adults, because children no longer transmit these serotypes. However, the frequency of disease caused by serotypes not targeted by the PCVs has increased and will continue to increase, particularly in adults. Consequently, there is a critical need for a new PCV formulation that targets the remaining serotypes that are expected to cause the most disease in adults. The proposed projects will address a major challenge?predicting which of the 80+ serotypes that are not included in current PCVs are most likely to become important causes of disease in adults in the future. To make such predictions about disease patterns in adults, it is necessary to know which non-vaccine serotypes will emerge to colonize the nasopharynx of healthy children, who are the main source of exposure for adults. Likewise, it is critical to understand which non-vaccine serotypes that colonize vaccinated children are likely to cause disease in adults. To answer these questions, we will first develop and validate a statistical model to predict which serotypes will colonize healthy vaccinated children based on both empirical epidemiologic data and novel experimental data. The experimental data for these models will be collected using an innovative, high-throughput in vitro assay of serotype competition (a known correlate of frequency of colonization) in which large numbers of serotypes will be grown in nutrient-limited media. The relative abundance of the serotypes in these competitions will be tracked using Illumina sequencing. The models will be developed and validated using colonization data from the Navajo Nation and from Denmark from both before and after introduction of PCVs in children. Because serotypes differ in their capacity to cause disease, it is important to know how projected changes in carriage of different serotypes among children will impact serotype-specific rates of disease in adults. Using large clinical databases on carriage and disease from the Navajo Nation and from Denmark, we will fit and validate an empirical model to determine, for different serotypes, how both the capacity to cause disease and serotype-specific frequency of colonization in children interact to influence serotype-specific disease rates in adults with or without underlying diseases. Finally, we will use the validated model to make projections of the serotype-specific rates of disease in adults following introduction of different PCVs in children (e.g., the planned PCV15) and will use this information to determine the potential impacts of alternative formulations of adult-specific conjugate vaccines. These studies will provide important new information that will inform the selection of serotypes for a new adult-specific pneumococcal conjugate vaccine, which should have a major impact on pneumococcal disease in adults.